Biopharmaceutics &

Pharmacokinetics | Module/PPt Based

LADMER SYSTEM

- is a way of understanding what goes on in the body

when any compound that has an effect on the body
is administered or ingested.
Unit 1: Introduction to Biopharmaceutics - is key for us because it is the qualitative way of
understanding drug action in a general way.
Key Terms
 Drugs - substances intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease
 Drug product performance - the release of the drug
substance from the drug product either for local drug
action or for drug absorption into the plasma for systemic
therapeutic activity
 Route of administration- way or proper entry of the drug
to be administered in the body
 LADMER- Liberation, Absorption, Metabolism, Excretion
and Response
 Hydrophilic- water loving
 Hydrophobic- water fearing
 Bioavailability- the rate and extent in which the drug
reaches the systemic circulation
 Biopharmaceutics- the study of physicochemical factors in
drug product formulation influencing bioavailability
 Pharmacokinetics - the science of the kinetics of drug
absorption, distribution and elimination
 Pharmacodynamics - the study of the biochemical and
physiological effects of drugs on the body

BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT

DESIGN
1. Therapeutic Objective
2. Drug (API)
3. Route of Administration
4. Drug Dosage and Dosage Regimen
5. Type of Drug Product
6. Excipients Biopharmaceutic Pharmacokinetic Pharmacodynamic
7. Method of Manufacture s s s
Liberation Absorption Response
IT INVOLVES FACTORS THAT INFLUENCE: Absorption Distribution Toxicity
a. the design of the drug product Metabolism
b. stability of the drug within the drug product Excretion
c. the manufacture of the drug product
d. the release of the drug from the drug product
1. Liberation - the exit of active pharmaceutical ingredient
e. the rate of dissolution/release of the drug at the
from the drug dosage form
absorption site
2. Absorption - process of uptake of the drug from the site
f. delivery of drug to the site of action
of administration into the systemic circulation

Major Area of Pharmacology Factors affecting drug absorption

Area Description
Pharmacodynamic What the drug does to the a) Physicochemical properties of the drug molecule
body - solubility, partition coefficient, pH, ionization of drug
Pharmacokinetics What the body does to the etc.
drug b) Nature of the drug product
Pharmacotherapeutics Study of the use of drugs in - formulation factors such as disintegration time,
treating disease manufacturing variables, nature and type of dosage
Pharmacy Science of preparing and forms etc.
dispensing medicines c) Anatomy and physiology at the site of drug absorption
Posology Study of the amount of drug - cell membrane physiology, gastrointestinal
that is required to produce physiology and clinical factors.
therapeutic effects
Toxicology Study of the harmful effects 3. Distribution - drug leaves the systemic circulation and
of drugs to living tissue
enters the cell

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 Biopharmaceutics &
4.  Drugs may be transported by several mechanisms
Pharmacokinetics | Module/PPt Based proteins, drugs bound to proteins and macromolecules
do not easily cross cell membranes
Metabolism - converts drugs into water  Nonpolar lipid soluble drugs traverse cell membranes
soluble, less toxic and inactive metabolites easily than do ionic or polar water-soluble drugs
5. Excretion - final elimination or loss of the drug from the (e.g. rifampicin)
body  Low molecular weight drugs diffuse across a cell
6. Response - how the patient react with this endogenous membrane more easily than do high molecular weight
substance that enters and excrete the body drug (e.g. heparins)

Drug release Absorption Drug in systemic Drug in PHARMACOKINETICS

and distribution circulation tissues
 DRUG ADMINISTRATION
Elimination Local – action of drug is near the site of administration
 Local anesthetics
Excretion and Pharmacologic
metabolism or clinical effect
 Topical ointments/creams
 Inhaled bronchodilators
FIGURE 1-1 Scheme demonstrating the dynamic relationship  Rectal suppositories
between the drug, the drug product, and the pharmacologic  Enemas for catharsis
effect.
Systemic - drug action is at a different site other than the
Drug delivery systems (DDS) site of administration
 are defined as methods by which drugs are delivered
to desired tissues, organs, cells and subcellular organs  Oral analgesics- act in CNS/ pain receptors
for drug release and absorption through a variety of  Transdermal nitroglycerin- act on coronary arteries
drug carriers.  Subcutaneous Low Molecular Weight Heparin
 Purpose of DDS - systemic anticoagulant
 to improve the pharmacological activities of Extravascular Intravascular
therapeutic drugs (Outside the cardiovascular (within cardiovascular
 to overcome problems such as limited solubility, system) system)
drug aggregation, low bioavailability, poor Examples: Examples:
biodistribution, lack of selectivity,  PO (oral)  IV (intravenous)
 to reduce the side effects of therapeutic drugs.  SC (subcutaneous)  IA (intrarterial)
 Rectal  IC (intracardiac)
 General Principles  Opthalmic
- A cell membrane is a semi permeable membrane
- structure composed primarily of lipids and
proteins B. ROUTE OF ADMINISTRATION
 2 layers of phospholipids between two surface layers Direct Routes of Administration
of proteins Oral Route
 hydrophilic head groups of the phospholipids facing - To be swallowed
the protein layers - Undergoes first-pass effect
 hydrophobic tail groups aligned in the interior e.g tablet, syrup, suspension
Advantage/s Disadvantage/s
 The fluid mosaic model (by Singer and Nicolson) explains  natural,  slow drug response
the transcellular  uncomplicated  chance of irregular
 convenient absorption of drugs
 safe  destruction of certain
drugs by the acid
reaction of the
stomach or by GI
enzymes
Buccal
- place between gums and cheeks to dissolve
diffusion of polar molecules; it considers that the cell
- Usually for longer acting preparations
membrane consists of globular proteins embedded in a
(slow release analgesics)
dynamic fluid, lipid bilayer matrix

Advantage/s Disadvantage/s
 Avoid first pass  Not for children
metabolism  Eating and drinking
 Permeation is faster difficulty
 Easy administration and  Drugs unstable at
removal (termination) in buccal pH (6.5-7)
case of toxicity

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 Biopharmaceutics &
Pharmacokinetics | Module/PPt Based Advantage/s Disadvantage/s
 Application is local  Inefficient and could
Sublingual  Effect is systemic be slow
- under the tongue
- For rapid acting preparations
(SL nitroglycerin, nifedipine) Other Routes
o Topical –application of drug on skin or mucous
Advantage/s Disadvantage/s membranes for local effect
 bypass first pass effect  don’t work for drugs o Optic (eyes)
and rapid acting that need to be o Otic (ears)
processed slowly by o Urethral (urethra)
your system o Vagina
e.g. Extended release o Intraarticular (placed directly into a joint)
drugs o Intraosseous (directly into the marrow of a bone)
Rectal Route
- Rectal suppositories or retention enemas (not
frequently used because of the development of
parenterals)
- Importantly used in pedia and geriatrics
- Used in cases the patient is vomiting and cannot
take in oral dosage forms
Advantage/s Disadvantage/s
 Used for children  Inconvenient
 Little or no first pass  Absorption is slow
effect  Irritation or
 Used in vomiting or inflammation of rectal
unconscious mucosa
Inhalational
- Through mouth (intranasal –nose)
- Takes advantage of the large surface area of the
lungs
- Intended for local (e.g. steroids for rhinitis or
asthma) and systemic (e.g. general anesthetics)
-
Advantage/s Disadvantage/s
 Local delivery,  Irritant effects on
potentially higher airways Absorption is
concentration of slow
medication in the target  Limitation of
organ medication dose due
 Avoidance of systemic to airway symptoms
adverse effects  May be very costly
 Vasodilation improves
and gas exchange

Indirect Routes of Administration

By Puncture
Parenterals (don’t undergo first-pass effect)
- Examples: IV, IM, SC, ID, IA, IP, IO, IT, Intraarticular
- IV, IA, IC -> thru intravascular
Advantage/s Disadvantage/s
 100% bioavailability  Painful
 Fastest method of drug  Required train
delivery personnel
 Alternative to  Cannot be withdrawn
unsuccessful oral once injected
Through the skin (percutaneous)
Percutaneous absorption
- Ex: transdermal patches

NOTE: Percutaneous is NOT a topical

 Percutaneous - systemic effect
 Topical - for local effect

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 Biopharmaceutics & Pharmacokinetics
Module/PowerPoint Based

Unit 2: Rates and Order of Reaction

Key Terms

 F= bioavalability
 k= rate constant, it represents the fraction of drugs
that is eliminated from the body during the given
period of time.
 Reaction Kinetics- a branch of chemistry that deals
with the rate of chemical reactions, with factors
influencing such rates, and with applications of rate
studies to elucidate the mechanism of reactions-
compare order of a reaction.
 Reaction Rate- velocity at which a reaction occurs
 Reaction Order- the way in which the concentration
of drug/reactant influences the rate of reaction

ORDER OF KINETICS  Zero Order Elimination- The same amount of drug is

eliminated per unit of time. REGARDLESS of the plasma
1. ZERO ORDER KINETICS
concentration of the drug rate of elimination is constant.
- Rate of reaction is independent of the concentration
Example: 2mg are eliminated per minute
of the drug remaining
Formula:  First Order Elimination- The same proportion of the drug
is eliminated per unit of time. This leads to a variable
amount eliminated based on the plasma concentration.
As the concentration drops the elimination rate drops as
well.
 C= concentration
Example: 2% of the available drug is eliminated per
 k0= zero order rate constant
minute
(unit: C/t example: mg/hr)
 t= time
 C0= initial concentration
Half-life (t ½)
 time it takes for the drug concentration to decrease
by 50%

1. ZERO ORDER HALF LIFE

2. FIRST ORDER KINETICS

- Rate of reaction is dependent of the concentration of Example:
the drug remaining
 C=concentration Based from the above data (from the problem of zero
 k= first order rate constant (unit: 1/t) order kinetics) the following given are obtained:
 t= time
 Co= 100 mg/ml (concentration at time zero)
 C0= initial concentration
 C= 70 mg/ml (the concentration based on the last
Formula: data given in the table)
 t= 12hr (time of the last concentration) constant
 k0= 2.5mg/hr

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 Biopharmaceutics & Pharmacokinetics
Module/PowerPoint Based

2. FIRST ORDER SHELF LIFE

Example: Based from the data obtain from the above

2. FIRST ORDER HALF LIFE problem the following given is obtained

BIOAVAILABILITY

→ the proportion of a drug or other substance which enters

the circulation when introduced into the body and so is able
to have an active effect

Factors:

1. Pharmaceutical factors
2. Patient related factors
3. Route of administration
Shelf Life (t90)
Methods of Assessing Bioavailability
 as the time necessary for the drug to decay to 90%
of its original concentration.

1. ZERO ORDER SHELF LIFE

Example: Based from the above problem the following

given are obtained

Co= 100 mg/ml k0= 2.5mg/hr Using plasma data

 Tmax
- time of peak plasma concentration the time required
to reach the maximum drug concentration after drug
administration
 Cmax
- maximum concentration maximum plasma drug
concentration obtained after oral administration of
the drug
- Indicates that the drug sufficiently and systematically
absorbed to provide a therapeutic response
- Approximate the absorption rate of a drug
 MEC
- minimum effective concentration

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 Biopharmaceutics & Pharmacokinetics
Module/PowerPoint Based

- Lowest concentration which exerts pharmacologic

effect
 MTC
- minimum toxic concentration
- Lowest concentration which exhibits toxicity
 Onset of action
- time from administration to when the drug
concentration reaches the
 MEC
- Duration of action
- length time in which the drug concentration remains
above the MEC
 Therapeutic window
- the distance between the MEC and MTC; larger Sample Problem:
therapeutic window = safer
 AUC Given the data below, compute for the 𝑨𝑼𝑪�→∞ using
- Area under the curve trapezoidal rule.
- Measure of quantity of drug in the body
- Measures the extent of bioavailability
- It is directly proportional to the dose
- Unit: μg/ml.hrs or μghrs/ml (concx time)

Area Under the Curve Methods to estimate AUC

 Counting the squares

 Weighing method

Methods for more accurate AUC

 Trapezoidal rule –most used Solution

 Using blood level equations

The figure above shows when will the drug will elicit its
onset of action on specific time until it reaches its
maximum activity up until it will be depleted in the
system.

Area Under the Curve Trapezoid Rule

 Compute for the individual area of the trapezoids.

 Total AUC = 0 →infinity
 Infinite time – time beyond which the area is
insignificant

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 Biopharmaceutics & Pharmacokinetics
Module/PowerPoint Based

Where:

 Cp= plasma concentration

Body Fluids for a 70-kg person:

Volume (L)
Intracellular fluid 28
Extracellular
Intercellular fluid 10
Plasma 4
Total 42

FIRST ODRDER KINETICS VERSUS ZERO ORDER KINETICS

First order kinetics refers to Zero order kinetics refers to
chemical reactions whose chemical reactions whose
rate of reaction depends on rate of reaction does not
the molar concentration of depend on the reactant
VOLUME OF DISTRIBUTION one reactant concentration
Graph of reactant Graph of reactant
 Hypothetical volume of fluid into which a drug is
concentration vs. time is a concentration vs. time is a
dispersed
curved graph linear graph
 Plasma compartment Reactions depend on the Reactions do not depend on
- 6%, about 4 L in a 70-kg adult reactant concentration the reactant concentration
- High MW weight drugs Rate law includes the rate Rate law includes only the
 Extracellular fluid constant multiplied by the rate constant
- 20%, about 20 L in a 70-kg adult reactant concentration
- Low MW drugs, hydrophilic
 Total body water
- 60%, about 42 L in a 70-kg adult

Apparent Volume of Distribution

Example:

If 100mg of drug was administered and resulted to plasma

concentration of 0.02mg/ml, what is the volume of
distribution?

Solution:

- Substitute all the given based from the problem

- Given: Dose=100mg; Cp=0.02mg/ml

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 Biopharmaceutics &
Pharmacokinetics | Midterm III High Low Drug permeability is
limited. Bioavailability
may be incomplete if
drug is not released and
dissolved within
Unit 3: Biopharmaceutical Consideration in absorption window
IV Low Low Difficulty in formulating
Drug Product Design a drug product that will
deliver consistent drug
Drugs are not usually given as a pure chemical drug bioavailability. An
substance, but are formulated into a finished dosage forms alternate route of
(drug products), such as tablets, capsules, ointments, administration may be
solutions, etc, which are then administered to patients. Drug needed.
products are designed to deliver the drug for local or systemic
effects. The design of the dosage form, the formulation of the 3. Particle size and surface area
drug product, and the manufacturing process requires a o Smaller particle size  higher dissolution  better
thorough understanding of the biopharmaceutic principles of absorption
drug delivery. o Decrease Particle Size  increase Surface Area 
Considerations in the design of a drug product to
increase dissolution  increase bioavailability
deliver the active drug with the desired bioavailability
o Drug product must have uniform particle size to have a
characteristics and therapeutic objectives include the
predictable absorption
physicochemical properties of the drug molecule, the type of
drug product (eg, tablet, capsule, transdermal delivery
4. Partition coefficient
system, topical ointment, parenteral solution), the nature of
o Ratio of solubility in oil: solubility in water
the excipients in the drug product, the method of
o Use of separatory funnel with n-octanol (oil) and water
manufacturing, and the route of drug administration.
o High part coefficient = more lipid soluble (better
absorbed)
KEY TERMS
 Ionization- process in which an atom or a molecule gains
or loses electrons to form charged ion 5. Extent of ionization
 Stereoisomer- differ in spatial arrangement of atoms o A Nonionized drug is lipid soluble  better
 Enantiomer-chiral molecules that are mirror images of absorbed
one another o Henderson Hasselbalch equations
 GET- gastric emptying time
 GER- gastric emptying rate

Consideration in Drug Product Design

PHYSICOCHEMICAL PRINCIPLES
1. Solubility
o Extent to which a drug dissolves
o Maximum amount of solute dissolved in a solvent at Ionized
equilibrium %Ionization = x 100 %
o Drugs must be water soluble to dissolve in aqueous
Ionized +Unioinized
media of stomach
Note: Ionized form of drug is the one that is excreted (salt
form) Unionized form of drug is the one that is absorbed by
the body (acid/basic form of drug)

2. Dissolution Sample Problem:

o The rate at which the drug/formulation dissolves 1. What is the pH of the solution for 0.01M benzoic acid
and 2.3 x 10-3 M of sodium benzoate?
Class Solubilit Permeability Comments Ka of benzoic acid= 6.5 x 10-5
y Given:
I High High Drug dissolves rapidly Ka of benzoic acid= 6.5 x 10-5
and is well absorbed. Acid (benzoic acid)= 0.01M
Salt (sodium benzoate)= 2.3 x 10-3 M
II Low High Drug dissolution limited
and well absorbed. Solution:
Bioavailability is
controlled by the dosage salt
form and rate of release pH= pKa+ log
of drug substance
acid

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 Biopharmaceutics &
Ionized
Pharmacokinetics | Midterm %Ionization = x 100 %
Ionized +Unioinized
pKa=−log Ka Ionized: 4.5 x 10−6
−5
pKa=−log 6.5 x 10 Unionized: 3.3 x 10−4
−5
pKa=−log 6.5 x 10
pKa=4.19 4.5 x 10−6
%Ionization = −6 −4
x 100 %
4.5 x 10 +3.3 x 10
salt %Ionization = 0.013 %
pH= pKa+ log
acid %unionized= 100%- 0.013%= 99.99%

2.3 x 10−5 Therefore, 0.013% of drug is excreted and 99.99% of the drug
pH=4.19+ log is absorbed in the body
0.01

pH=4.19−2.64
pH=1.55 General pattern: acidic drugs better absorbed in stomach
(since in Nonionized form) and basic drugs better absorbed in
small intestine (nonionized form)
2. What is the percent ionization of the above problem?

Ionized
%Ionization = x 100 %
Ionized +Unioinized
6. Salt formation
o In general, salt forms are more water soluble than
Ionized: 2.3 x 10−5 free drugs (morphine vs morphine sulfate)
Unionized: 0.01 o Higher water solubility  faster dissolution
2.3 x 10−5
%Ionization = x 100 % 7. Polymorphism
2.3 x 10−5 +0.01
%Ionization = 0.25 % o Arrangement of a drug substance in various crystal
forms/polymorphs
%unionized= 100%-0.25%= 99.75% o Crystalline –more stable  decreased
solubility due to rigid structure
Therefore, 0.25% of drug is excreted and 99.75% of drug is o Amorphous –less stable  increased
absorbed solubilty
Ex. Insulin –crystalline used for long acting (glargine);
amorphous forms for short acting (lispro, aspart); mixture of
3. Calculate the pH of the solution of NH3 3.3 x 10-4 and NH4CI crystalline amorphous
4.5 x 10-6. Kb of ammonia 1.8 x 10-5  (70:30) for intermediate acting (Insulin NPH)

Given 8. Chirality
Base (NH3)= 3.3 x 10-4 o Type of molecule that has a non superimposable
Salt (NH4CI)= 4.5 x 10-6 images
Kb= 1.8 x 10-5 o Ability of drug to exist as optically active (R or S)
stereoisomers or enantiomers
o Racemate: mixture of R and S forms
base o Ex. Ibuprofen
pH=14−[ pKb+log ]
salt o S-ibuprofen –pharmacologically active
pKb=−log Kb o R-ibuprofen –inactive
pKb=−log 1.8 x 10−5 Other drugs available as different forms (Omeprazole and
pKb=4.7 ESomeprazole; Citalopram and EScitalopram)
base
pH=14−[ pKb+log ]
salt 9. Hydrates
o Hydrated forms are usually more stable (crystalline
3.3 x 10−4
pH=14−[4.7+log ] structure), less soluble than amorphous
4.5 x 10−6 10. Complex formation
−4
3.3 x 10 o Process where the drug molecule combines with the
pH=14−[4.7+log ] receptor molecule to form a complex
4.5 x 10−6
o Chelates –complexes that involve ring like structure
pH=14−[4.7+1.87]
formed by interaction
pH=14−[6.57 ] o Ex: tetracycline + Ca  decreased solubility;
pH=7.43 ¿ less absorption
o Ex: cyclodextrinchelates  increase
4. What is the percent ionization of the above problem solubility; higher absorption

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 Biopharmaceutics & Amoxicillin Acetaminophen Hydralazine Chlorpropamid
Pharmacokinetics | Midterm Ampicillin Cefaclor Hydrochlorothiazide e
Aspirin Cephalexin Metoprolol Glibenclamide
Isoniazid Digoxin Oxazepam Glipizide
Levodopa Potassium ion Phenytoin Metronidazole
Furosemide Sulfadiazine Propoxyphene Prednisone
Penicillin G Sulfadimethoxine propranolol
PHYSIOLOGIC FACTORS Tetracycline Sulfanilamide Theophylline
1. Gastric emptying time/ Gastric emptying rate Rifampin Sulfasymazine
o Inversely related Doxycycline Sulfisoxazole
o Short gastric emptying time = less time for drug to
stay in the stomach to move to small intestine for
absorption 4. Blood perfusion
o High gastric emptying RATE = faster travel time to o Related to high surface area of small intestines
small intestine for absorption o Intestines are highly perfused with blood vessels
o Short gastric emptying time = high gastric emptying o Higher absorption for drugs
RATE = better absorption
o Some drugs can effect gastric emptying time/rate
FORMULATION FACTORS
 Anticholinergics –increase GET/ slow GER
 Prokinetics (domperidone; metoclopramide)  Compatibility of excipients and drugs
-decrease GET/ faster GER  Particle size
 Disease states/ age of patient can also affect  Excipients
gastric emptying (geriatrics have slower gastric  Coating: protects drug; decreases rate of
emptying rate than young) disintegration
 Lubricants: hydrophobic  too much will decrease
dissolution
 Disintegrants: too little  tablet will not disintegrate
 Disintegration
- Governed by NOYES-WHITNEY equation

Normal GET: approx2 hrs (advise drugs to be taken 2 hrs RATE LIMITING STEPS FOR TABLETS
before or 4 hrs after meals for drugs affected by food)
TABLET  GRANULES  AGGREGATES  AQUEOUS
Increase GET Decrease GET SOLUTION  ABSORPTION
Cold foods/beverages Hot foods/beverages
Lying on the left side Lying on the right side Schematic Diagram where the tablet dissolves up until it will
Anticholinergics, Narcotics, Prokinetics be absorbed by the system
ethanol
(Metoclopramide,  Rate limiting for solutions = absorption
Domperidone,  Capsules, suspensions, modified release preparations,
Erythromycin, Bethanechol) tablets  undergo LIBERATION since drug is not yet in
Fatty acids, triglycerides solution form for absorption
Diabetes, PUD
Bioavalability- Rate & extent of therapeutically active drug
that reaches the general circulation
2. pH in GIT
o Stomach acidic
- Basic drugs are ionized
 Tmax
- Acidic drugs are NON-ionized
- time of peak plasma concentration the time required
- Acidic drugs expected to be better absorbed
to reach the maximum drug concentration after drug
o Small intestine
administration
- Basic drugs are NON-ionized
 Cmax
- Acidic drugs are ionized
- maximum concentration maximum plasma drug
- Basic drugs expected to be better absorbed
concentration obtained after oral administration of
3. Interaction with GI contents
the drug
o Food can increase or decrease absorption
- Indicates that the drug sufficiently and systematically
o In general; slower absorption of drugs taken with absorbed to provide a therapeutic response
meals - Approximate the absorption rate of a drug
o Metal cations can chelate with drugs (tetracycline,  MEC
fluoroquinolones), decreasing absorption - minimum effective concentration
o Fatty meals increase griseofulvin - Lowest concentration which exerts pharmacologic
absorption effect
 MTC
- minimum toxic concentration
Drugs whose absorption is reduced, delayed, increased, - Lowest concentration which exhibits toxicity
or not affected by the presence of food.  Onset of action
Reduced Delayed Increased Not affected

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 Biopharmaceutics &
120 x 500
Pharmacokinetics | Midterm ℜ= x 100 %
125 x 500
- - time from administration
60 000
to when the drug concentration reaches the MEC ℜ= x 100 %
62500
 Duration of action
- length time in which the drug concentration remains ℜ=96 %
above the MEC
 Therapeutic window Absolute Bioavailability
- the distance between the MEC and MTC; larger Given:
therapeutic window = safer EV- tablet
 AUC IV-bolus
- Area under the curve
- Measure of quantity of drug in the body Solution:
- Measures the extent of bioavailability
- It is directly proportional to the dose AUC EV x DoseIV
AB= x 100 %
- Unit: μg/ml.hrs or μghrs/ml (concx time) AUC IV x Dose EV

Relative bioavailability 120 x 50

 Systemic availability of a drug from a dosage form as AB= x 100 %
17 x 500
compared to a reference standard given by the same
route of administration
 Innovator vs “me too” 6 000
 Extravascular route compared to another Extravascular AB= x 100 %
8500
route
AUC test x Dosestd
x 100 % AB=70.59 %
AUC std x Dosetest
Ex: AUC ophthalmic oint/ AUC opthalmicsolution
Bioequivalence
AUC tablet/ AUC capsule
 Relation in terms of bioavailability, therapeutic
response, or a set of established standards of one
drug to another
 Approaches:
Absolute bioavailability - In vivo pharmacokinetic studies
 F value - In vivo pharmacodynamics studies
- Fraction of drug systemically absorbed from the - Comparative clinical trials
dosage form - Comparative in vivo tests
*Biowaiver is granted for generic drugs
Formula:
F value = AUC po/ AUC IV
* IV is used since it is 100% bioavailable 1. Generic substitution
 Process of dispensing a different brand or unbranded
AUC EV x DoseIV drug product in place of the prescribed drug product
x 100 % that contains the same:
AUC IV x Dose EV - active ingredient or therapeutic moiety
- same salt or ester
Sample Problem: - same dosage form but is made of the different
Given the data below, compute for the absolute and relative manufacturer
and absolute bioavailability:
AUC Dose (mg)
IV bolus 17 50
Oral Tablet 120 500
Oral solution 125 500

Solution:
Relative Bioavailability
Given:
Test- tablet 2. Pharmaceutical alternatives
Standard- solution  same therapeutic moiety but as different salts,
AUC test x Dosestd esters, and complexes.
ℜ= x 100 % - e.g. Tetracycline phosphate or hydrochloride
AUC std x Dosetest equivalent to 250 mg Tetracycline base
- e.g. extended release & immediate release

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 Biopharmaceutics &
 Ensure the drug product is safe & effective for its
Pharmacokinetics | Midterm labeled indication for use prior to its marketing.

3. Pharmaceutical equivalents
Drug products that contain the same:
 active ingredient (same salt, ester, or chemical form)
 identical in strength/conc.
 dosage form
 route of administration

4. Pharmaceutical equivalents
 Also chemical equivalents
 Must meet identical standards (strength, quality,
purity and identity)
 Same:
- API
- Dosage form
- Dosage strength
- Mode of administration

5. Pharmaceutical substitution
 Process of dispensing a pharmaceutic alternative for
the prescribed drug product
 Requires physician’s approval
o e.g. Ampicillin suspension in place of
ampicillin capsules

6. Therapeutic alternatives
 Drug products containing different active
ingredients that are indicated for the same
therapeutic or clinical objective
 Active ingredient are from the same pharmacologic
class and are expected to have the same therapeutic
effect when given to patient with such condition
o e.g. Famotidine for ranitidine

7. Therapeutic substitution
 Process of dispensing a therapeutic alternative in
place of described drug product
o e.g. Amoxicillin instead of penicillin

Purpose of Bioavailability Studies

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 BIOPHARMACEUTICS AND PHARMACOKINETICS
Bs Pharmacy || 2021-2022 SUBJECT

ABSORPTION AND DISTRIBUTION

Route BA ADV DIS
Legend:
PARENTERAL
Remember Previous Trans
(Exams)
Lecturer Book
Trans Comm
Intravenous 100% Immediate Inc. chance
bolus effect of adverse
     (IV bolus) reaction
Intravenous 100% • Plasma drug Requires
Unit Outline infusion levels precisely skill of
(IV infusion) controlled insertion
1. Describe the physiologic factors affecting absorption. • May inject Tissue
2. Describe the routes of drug administration large fluid damage at
volumes the site of
3. Discuss the different transport processes for drug
• Drugs with injection
absorption poor lipid sol
4. Enumerate the relevant drug interactions concerning and irritating
absorption drugs
5. Describe the physicochemical parameters of drugs
affecting disposition Intramuscular Rapid Easier to inject Irritating
6. Describe the physiologic determinants of drug (IM) (Aqueous than IV Larger drugs may
disposition soln) Slow volume may be be painful
(non- used compared
7. Enumerate the different plasma protein binding site
aqueous to SC soln
1. CHECKLIST soln)
□ Read course outcomes Subcutaneous Prompt For insulin Depends on
□ Read course guide prior to class attendance (SC) from injection blood flow
□ Proactively participate in discussions aqueous and injection
soln Slow volume
□ Watch videos related to the topic
absorption
□ Participate in discussion board (Canvas) from
□ Answer and submit course unit tasks repository
formulation
REQUIRED READINGS/ VIDEOS
□ Please watch the following videos thru the given link.
□ https://www.youtube.com/watch?v=J5pWH1r3pgU ROUTE BA ADV DIS
□ https://www.youtube.com/watch?v=1SHszPMSRQA
□ NOTE: This has been assigned to you by your instructor ENTERAL
during the previous meeting. Buccal or Rapid abs No “First Not for most
Sublingual from lipid Pass Effect” drugs with
ABSORPTION soluble higher
drugs doses
■ the process of uptake of the compound from the site of Oral (PO) Abs may Safest and • Some may
administration into the systemic circulation. vary Slower easiest have erratic
■ Covers a drug’s progress from the time it’s administered, absorption route abs • First
through its passage to the tissues, until it becomes available for compared to pass effect
use by the body. IV
Adsorption Rectal Abs may For patient • Supp may
■ Bound to the surface of the skin or vary who cannot migrate to
mucosa swallow different
Penetration position
■ Drug reaches the deepest layer of the skin, yet does not • discomfort
reach the blood capillaries
Sorption
■ Penetration and permeation
Aqueous solution
■ Prerequisite for absorption

Common Routes of Drug Administration

■ Parenteral
■ Enteral
■ Transdermal
■ Inhalation and Intranasal

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 BIOPHARMACEUTICS AND PHARMACOKINETICS- Absorption and Distribution
Types of Absorption
ROUTE BA ADV DIS ■ Transcellular
OTHER  Process of drug movement across the cell
■ Paracellular
Transdermal • Slow abs • Easy to use Irritation  Process of drug movement that goes through gaps or
• Inc abs • Used for Permeability tight junction between cell
with lipid-soluble vary Type of
occlusive drugs with low cream or DRUG ABSORPTION REQUIRES THE DRUG TO BE
dressing dose and low ointment base TRANSPORTED ACROSS VARIOUS CELL MEMBRANES
MW affects drug
release Cell membrane
■ or plasma membrane
■ The outermost layer of a cell
Inhalation Rapid abs For local or • Particle size ■ A semipermeable structure composed primarily of lipids and
and systemic determines proteins
intranasal effects anatomic ■ Generally thin, approximately 70 to 100 A in thickness.
placement in ■ Primarily composed of:
respiratory  lipid
tract  protein
• Stimulate Parts of Cell Membrane:
cough reflex ■ Phospholipid: 1 head and 2 tails
 Polar head attract water - hydrophilic
SITES OF ABSORPTION  Non-polar tails repel water -hydrophobic
■ Buccal ■ Cell surface proteins
■ Sublingual  a. Channel proteins - transport food and other
■ Gastrointestinal molecules into the cell and transport wastes out of the
■ Percutaneous cells.
■ Subcutaneous  b. Receptor proteins - gather information about the
■ Intramuscular
cell’s surroundings
■ Intraperitoneal
 c. Cell surface markers - identify the type of cell,
■ Intracutaneous
important for cell recognition
■ Ocular
■ Permeability of the cell membrane
■ Nasal
 1. Semi permeable/selectively permeable - only
■ Pulmonal
certain substances can pass across the membrane.
■ Rectal
 2. Factors that determine whether a molecule can
pass through a membrane or not:
PHARMACEUTIC FACTORS AFFECTING DRUG
 a. size
BIOVAILABILITY
 b. type (polar, non-polar)
■ Major functions:
■ the type of drug product (eg, solution, suspension,
 Hold together the aqueous cell contents (structure)
suppository)
■ the nature of the excipients in the drug product  Separate cellular contents from the aqueous external
■ the physicochemical properties of the drug molecule fluid (barrier)
 Control transport of substances in and out of the cell
The nature of the excipients (regulation)
Ø binder  Respond to the environment
Ø Disintegrants
Ø Lubricants Theories of cell membrane
■ Lipid bilayer or unit membrane theory
Physical and chemical nature of the active drug  composed of two layers of phospholipids between two
Ø Particle size surface layers of proteins
Ø Polymorphism ■ Fluid mosaic model
Ø Solvates  consists of globular protein embedded in a dynamic
Ø Ionization fluid, lipid bilayer matrix
 proteins embedded in a phospholipid bilayer.
Systemic absorption of drug is dependent on
■ Physicochemical properties of the drug
 Surface area, solubility, Partition coefficient
■ Nature of the drug
■ Anatomy and physiology of the drug absorption

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 BIOPHARMACEUTICS AND PHARMACOKINETICS- Absorption and Distribution
PASSAGE OF DRUGS ACROSS CELL MEMBRANE Connective (Pore) Transport
Absorption Mechanism ■ AKA: paracellular transport
Transport Mechanism ■ Movement of a compound across membranes by way of
passages between the cells
Transport Mechanism ■ Drug molecules dissolved in aqueous medium at the
■ Passive transport absorption site move along the solvent through the pore.
■ Carrier Mediated Transport ■ Very small molecules
 Active transport ■ transport protein
 Facilitated transport  may form an open channel across the lipid membrane
■ Convective transport of the cell
■ Vesicular transport ■ Drug transport across tight (narrow) junctions between cells
 Phagocytosis or trans-endothelial channels of cells
 Pinocytosis Examples
■ Ion Pair transport  Inorganic and organic electrolytes up to 150 to
400MW
Transport Mechanisms- moving material in and out of the cell  Ions of opposite charge of pore lining u
Concentration gradient - the difference in the amount of a  Ionized sulfonamides
substance inside and outside of the cell
1. Going “with the gradient” Ion Pair Transport
2. Going “against the gradient” ■ The absorption of some highly ionized compounds at
3. Equilibrium exists when the concentration of molecules is physiological pH cannot be explained by simple or passive
the same throughout a space (inside and outside the cell) diffusion or any other existing hypothesis of absorption
■ Strong electrolytes drugs are highly ionized or charged
PASSIVE DIFFUSION molecules, penetrate membranes poorly
■ the passage of molecules through a membrane which Examples
behaves inertly.  Quaternary ammonium compounds
→ along the concentration gradient  Sulfonic acids
→ Fick’s first law
► states that the rate of diffusion is proportional to the Vesicular Transport
difference in drug concentration on both sides of the ■ Is the process of engulfing particles or dissolved materials by
membrane. the cell.
■ process by which molecules spontaneously diffuse from a ► Endocytosis
region of higher concentration to a region of lower ► Pinocytosis
concentration ► Phagocytosis
■ major transmembrane process for most drugs. ONLY transport mechanism that DOES NOT REQUIRE the
■ ex. Osmosis -- passive diffusion of water across a permeable drug to be in a solution
membrane.
Examples of Passive Diffusion:
 Weak organic acids
 Weak organic bases
 Organic nonelectrolytes (alcohol, amidopyrine, urea)
 Cardiac glycosides

Carrier mediated: Active Transport

Characteristics:
 carrier-mediated transmembrane process
 across the concentration gradient
 from regions of low drug concentrations to regions of
high concentrations
 an energy-consuming system
■ plays an important role in the renal and biliary secretion of
many drugs and metabolites.
■ Na, K, I, hexoses, monosaccharides, amino acids, strong Endocytosis/Pinocytosis
organic acids and bases, cardiac glycosides, pyrimidine bases, Examples
testosterone, estradiol, 5-FU (5 fluorouracil), Fe, Ca ■ Fats, glycerin, starch
■ carrier-mediated transport system ■ Parasite eggs
■ along concentration gradient ■ Vitamins A, D, E and K
■ moves from a region of high drug concentration to a region of ■ Plastic particles, hairs and yeast cells
a low drug concentration ■ Ferritin and insulin
■ does not require energy ■ Sabin polio vaccine
■ saturable and structurally selective
■ shows competition kinetics for drugs of a similar structure

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 BIOPHARMACEUTICS AND PHARMACOKINETICS- Absorption and Distribution
ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS OF ■ Anthral milling
DRUG ABSORPTION ■ Empty stomach: 100 mL of gastric fluid
■ Maximum capacity: about 1.1 to 1.2 L
The major physiologic processes that occur in the ■ 3 types of glands
gastrointestinal system:  Mucous glands
■ Secretion  Chief (zymogenic cells)
■ Digestion  Parietal cells
■ Absorption ■ Gastrin release is regulated by stomach distension and the
presence of peptides and amino acids
֍ The most important site for drug absorption is the small ■ Stomach emptying influenced by the food content and
intestine. osmolality
■ Secretion – includes the transport of fluid, electrolytes, Small Intestine
peptides, and proteins into the lumen of the alimentary canal. ■ Duodenum
■ Digestion – is the breakdown of food constituents into ■ Jejunum
smaller structures in preparation for absorption. ■ Ileum
■ Absorption – is the entry of constituents from the lumen of ■ presence of proteolytic enzymes
the gut into the body. May be considered as the net results of ■ Amylase
both lumen-to-blood and blood-to-lumen transport movements. ■ Pancreatic lipase
■ Bile secretion: 250 – 110 mL/day
Components Of Total Transit Time (0.4 To 5 Days) ■ Pancreatic juice: 300 – 500 mL/day
■ gastric emptying Jejunum
■ small intestinal transit (3 to 4 hours; 7 hours) ■ Middle portion
■ colonic transit ■ Preferred IN VIVO drug absorption studies
4 – 8 hours → fasting state (S and SI) ■ Intestinal fluid: 3000 mL/day
8 – 12 hours → fed state (S and SI) Ileum
֍ the time it takes for food to pass through your entire ■ terminal part of the small intestine
digestive tract ■ has fewer contractions than the duodenum.
■ pH 7, with the distal part as high as 8
The normal physiologic process of the alimentary canal ■ Ileocecal valve – separates SI from LI
may be affected by: Colon
1. diet ■ lacks microvilli
2. contents of the GI tract ■ very limited in drug absorption due to the more viscous and
3. hormones semisolid nature of the lumen contents
4. the visceral nervous system ■ lined with mucin (lubricant and protectant)
5. disease ■ pH 5.5 to 7
6. drugs ■ Drugs that are absorbed well in this region are good
■ Primary Organs of the GI tract: candidates for an oral sustained-release dosage form
 Stomach ■ The colon contains both aerobic and anaerobic
 Small intestine (duodenum, jejunum, & ileum) microorganisms that may metabolized some drugs.
 Colon (large intestine) Rectum
■ 15 cm, ending the anus
Oral Cavity ■ Drug absorption is variable
■ Saliva
 main secretion; pH 7 DRUG ABSORPTION IN THE GASTROINTESTINAL
 1500 ml/day TRACT
■ Ptyalin – salivary amylase which digests starches
■ Mucin - lubricant ■ Drugs may be absorbed by passive diffusion from all parts of
Esophagus the alimentary canal including sublingual, buccal, GI, and rectal
■ connects the pharynx and the cardiac orifice of the stomach absorption.
■ pH 5 - 6 ■ For most drugs, the optimum site for drug absorption after
■ esophageal sphincter oral administration is the upper portion of the small intestine or
 which prevents acid reflux from the stomach duodenum region.
Gastrointestinal Motility
■ Very little drug dissolution occurs in the esophagus ■ GI motility tends to move the drug through the alimentary
■ Tablets and capsule that lodge in this area causing irritation canal so that it may not stay at the absorption site.
Stomach ■ The transit time of the drug in the GI tract depends upon the
■ innervated by the vagus nerve pharmacologic properties of the drug, type of the dosage form,
■ Fasting state - pH 2 to 6 and various physiologic factors.
■ Fed state – pH 1.5 to 2 ■ Physiologic movement of the drug within the GI tract depends
■ Stomach acid secretion is stimulated by gastrin and upon whether the alimentary canal contains recently ingested
histamine food or is in fasted or interdigestive state.
■ Primary purpose: to grind food and mix it with acidic gastric
acid
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 BIOPHARMACEUTICS AND PHARMACOKINETICS- Absorption and Distribution
Gastric Emptying Time 2. The Lymphatic circulation in drug absorption is well
■ Duodenum --- has the greatest capacity for the absorption of absorbed. Drugs are absorbed through the lacteal or lymphatic
drugs from the GI tract vessels under the microvilli
■ a delay in the gastric emptying time for the drug to reach the ■ bypasses the first-pass effect
duodenum will slow the rate and possibly the extent of drug ■ important in the absorption of dietary lipids
absorption, thereby prolonging the onset time for the drugs. ■ partially responsible for the absorption for some lipophilic
↑GET, ↓GER, ↓ABS ↓GET, ↑GER, ↑ ABS drugs
Fatty meal Cold foods Effect of food on Gastrointestinal Drug Absorption
Hot meal Mild exercise ■ The presence of food in the GI tract can affect the
Stress Motility bioavailability of the drug
Lying on the left Lying on the right ■ Digested food contains amino acids, fatty acids, and many
side side nutrients that may affect intestinal pH and solubility of drugs.
Heavy exercise Standing position ■ The absorption of some antibiotics is decreased with food
Anti-motility ■ Griseofulvin (better absorbed when given with food containing
a high fat content)
Factors Affecting Gastric Emptying Rate ■ Fasted state
1. Volume ■ Enteric-coated tablets
2. Type of meal Effects of food on the bioavailability of a drug product
Fatty acids ■ Delay in gastric emptying
Triglycerides ■ Stimulation of bile flow
Carbohydrates ■ A change in the pH of the GI tract
Amino acids ■ An increase in splanchnic blood flow
3. Osmotic pressure ■ A change in luminal metabolism of the drug substance
4. Physical state of gastric content ■ Physical and chemical interaction of the meal with the drug
5. Chemicals product or drug substance
Acids Double-peak Phenomenon
Alkali (NaHCO3) ■ The double-peak phenomenon is generally observed after the
6. Drugs administration of a single dose to fasted patients
Anticholinergics ■ Food can also affect the integrity of the dosage form causing
Narcotic analgesics an alteration in the release rate of the drug
Metoclopramide ■ The rationale for the double-peak phenomenon has been
Ethanol attributed to variability in stomach emptying, variables intestinal
7. Miscellaneous motility, presence of food, enterohepatic recycling, or failure of
Body position a tablet dosage form.
Viscosity Methods for studying factors that affect drug absorption
Emotional states ■ Gamma Scintigraphy to Study Site of Drug Release
Bile salts ■ Markers to Study Effect of Gastric and GI Transit Time on
Disease states Absorption ■ Remote Drug Delivery Capsules
Exercise ■ Osmotic Pump Systems u In-Vivo GI Perfusion Studies
Gastric surgery ■ Intestinal Permeability to Drugs
Intestinal Motility Effect of disease states on drug absorption
■ Normal peristaltic movements mix the contents of the ■ Intestinal blood flow
duodenum, bringing the drug particles into intimate contact with ■ Gastrointestinal motility
the intestinal mucosal cells. ■ Changes in stomach emptying time
■ The drugs must have a sufficient time at the absorption site ■ Gastric pH that affects drug solubility
for the optimum absorption. ■ Intestinal pH that affects the extent of ionization
■ For modified-release or controlled dosage forms, which ■ The permeability of the gut wall
slowly release the drug over an extended period of time, the ■ Bile secretion
dosage form must stay within a certain segment of the intestinal ■ Digestive enzyme secretion
tract so that the drug contents are released and absorbed prior ■ Alteration of normal GI flora
to loss of the dosage form in the feces. Drug that affects absorption of other drugs
Perfusion of the Gastrointestinal Tract ■ Anticholinergic drugs
1. The Splanchnic circulation receives about 28% of the cardiac ■ Metoclopramide
output and is increased after meals. ■ Antacids
■ Cholestyramine
■ Vitamin D
small hepatic- systemic
liver Nutrients that Interfere with drug absorption
intestine portal vein circulation
■ Water-soluble vitamins
■ Grapefruit juice naringin → Enzyme inhibitor
Mesenteric
vessels

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 BIOPHARMACEUTICS AND PHARMACOKINETICS- Absorption and Distribution
DISTRIBUTION Drug accumulation
■ refers to the transfer of the drug from the blood to ■ Depends on
extravascular fluids and tissues.  blood and tissue affinity for the drug (reversible)
Drug distribution sites ■ Drugs with high tissue affinity tend to accumulate or
■ When a dose of drug enters the blood, the molecules are concentrate in the tissue
distributed throughout the body by the systemic circulation ■ Drugs with a high lipid/water partition coefficient tend to
1. Target site (receptor) for drug action accumulate in lipid tissue
2. Other (non-receptor) tissues Permeability of cell and capillary membranes
3. Eliminating organ (liver and kidney) ■ Cell membranes vary in their permeability characteristics
4. Non eliminating organs (Brain, Skin and muscle) depending upon the tissue
5. Placenta ■ liver and kidneys > brain
6. Milk via mammary gland ■ The sinusoidal capillaries of the liver are very permeable and
7. Bound to proteins allow the passage of large-molecular-weight molecules.
8. Deposited in fats ■ BLOOD BRAIN BARRIER
Circulatory system  layer of glial cells, which have tight intercellular
■ Arteries junctions, surrounds the capillary endothelial of the
 Carries blood to the tissue brain and spinal cord
■ Veins  Permeable to lipid soluble
 Carries blood to the heart Physiologic condition where cell permeability is altered
■ Average subject: ■ Burns
 70 kg, 5 liters of blood, 3 liters of plasma  alter the permeability of skin and allow drugs and
 cardiac output = 0.08 L/min x 69 beats/min larger molecules to permeate inward or outward.
■ Drug molecules rapidly diffuse through a network of fine ■ Meningitis
capillaries to the tissue spaces filled with interstitial fluid  Inflammation → inc permeability → enhance drug
Drug distribution uptake
■ generally rapid ■ The high blood flow within a capillary allows for intimate
■ most small drug molecules permeate capillary membranes contact of drug molecules with the cell membrane, providing for
easily rapid drug diffusion.
■ passage of drug molecules depends on
 physicochemical nature (drug and the cell (1) Drugs easily cross the capillaries of the glomerulus of the
membrane) kidney and the sinusoids of the liver hydrophilic drugs cross this
■ Lipid soluble drugs generally diffuse across cell membranes barrier slowly
(2) The capillaries of the brain are surrounded by glial cells that
more easily than highly polar or water-soluble drugs.
create a blood-brain barrier, which acts as a thick lipid
Diffusion and Hydrostatic Pressure membrane Polar and lonic
■ The process by which drugs transverse capillary membranes. (3) In disease states, membranes may become more
Hydrostatic Pressure- represents a pressure gradient permeable to drugs. For example, in meningitis, the blood brain
between the arterial end of the capillaries entering the tissue barrier becomes more permeable to the penetration of drugs
and the venous capillaries leaving the tissue. into brain.
■ Drug-molecule complex
Hydrostatic/ filtration Absorptive pressure- The
 Drug interact with plasma or tissue proteins or with
pressure- The higher lower pressure of the venous other macromolecules such as Melanin and DNA
pressure at the arterial end blood compared with the ■ Volume of distribution (VD)
of the capillary tissue fluid  Estimate the extent of drug distribution in the body
 Relates the plasma conc to the amount of drug
Tissue Perfusion and Initial Drug Distribution present in the body
■ After the drug molecules enter the bloodstream, the rate of  theoretical volume in which the total amount of drug
blood flow perfusion to each tissue and the affinity of the drug would need to be uniformly distributed to produce the
desired blood concentration of a drug
to accumulate in the tissue govern the pattern of drug
Vd = Dose
distribution. ----------
■ Tissues that receive the highest blood flow will rapidly Cp
equilibrate with the drug, whereas tissues that are poorly Drug distribution and Pharmacodynamics
perfused will equilibrate with the drug more slowly. ■ Pharmacodynamics response is influenced by
■ Blood flow is an important factor in determining the initial  Distribution of drug
distribution of drugs  Conc of unbound drug
 PERFUSION OR FLOW LIMITED ■ The dose of the drug and the dosage form must be chosen to
provide sufficiently high plasma drug concentrations so that an
o Drug diffuse rapidly across the membrane
adequate amount of drugs reaches the site of drug action at a
o Blood flow is the rate limiting step in proper rate.
distribution ■ The onset and intensity of drug action is influenced by the
 DIFFUSION OR PERMEABILITY LIMITED initial distribution of the drug and total dose of the drug given to
o Drug distribution is limited by slow diffusion the patient
of drugs cross the membrane ■ Onset of time depends on
 Rate of free drug that reaches the receptor (MEC)
■ Drug affinity
■ Intensity of action depends on
 Partitioning and accumulation of the drug to the tissue  Total drug concentration of the receptor and no of
■ Distribution half life receptors occupied by the drug
 source
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 BIOPHARMACEUTICS AND PHARMACOKINETICS- Absorption and Distribution
■ The duration of drug action is mainly influenced by the rate of Alpha acid glycoprotein (orosomucoid)
drug elimination ■ A globulin with a molecular weight of about 44,000 d
Plasma drug concentration ■ Plasma concentration is low (0.4 to 1%)
■ total drug concentration in the plasma, including both ■ binds primarily basic (cationic) drugs, highly lipophilic
proteinbound drug and unbound drug concentrations Examples: Propranolol, Imipramine, Lidocaine
Highly protein bound = less free drug= less Vd Lipoproteins
Less protein bound = larger free drug conc = larger Vd ■ Macromolecular complexes of lipid and proteins and are
Highly protein bound = less free drug = less effect classified according to their density and separation in the
BOUND = inactive ultracentrifuge.
Reduced overall clearance ■ Responsible for
t1/2 = increases  the transport of plasma lipids
 binding of drugs if the albumin sites become
■ Drug molecules may bind to plasma proteins saturated
■ Bound drugs are pharmacologically inactive ■ LDL, HDL, VLDL
■ free, unbound drug can act on target sites in the tissues, elicit Erythrocytes (RBC)
a biologic response, and be available to the processes of ■ May bind both endogenous and exogenous compounds.
elimination ■ Consist of about 45 % of the volume of the blood
Examples: Pentobarbital, Phenytoin, Flurazepam
Drug protein binding Globulins
■ Drug- protein binding ■ may be responsible for the transport of certain endogenous
 formation a drug protein complex. substances such as corticosteroids
 may be a reversible or irreversible process ■ has a low capacity but high affinity for the binding of these
■ Reversible DPB endogenous substances
■ Irreversible DPB Examples: Corticosteroid, Thyroxin, Vit B12, Vit ADEK
■ Irreversible drug-protein binding
 is usually a result of chemical activation of the drug, METHODS FOR STUDYING DRUG-PROTEIN BINDING
which then attaches strongly to the protein or ■ Equilibrium dialysis
macromolecule by covalent chemical bonding ■ Dynamic dialysis
 accounts for certain types of drug toxicity that may ■ Diafiltration
occur over a long time period as in the case of ■ Ultrafiltration
chemical carcinogenesis ■ Gel chromatography
■ Reversible drug-protein binding ■ Spectrophotometry
 binds the protein with weaker chemical bonds such as ■ Electrophoresis
hydrogen bonds or van der waals forces. ■ Optical rotatory dispersion and circulatory dichroism
Drug may bind to various macromolecular components in Drug-protein binding is influenced by a number of
the blood including: important factors:
■ Albumin 1. The drug
■ Alpha acid glycoprotein (orosomucoid) 2. The protein
■ Globulins 3. The affinity between drug and protein, including the
■ Lipoproteins magnitude of the association constant.
■ Erythrocytes (RBC) 4. Drug interactions competition for the drug by other
Albumin substances at a protein-binding sites.
■ protein synthesized in liver (MW:65,000 to 69,000 D) 5. The pathophysiologic condition of the patient.
■ Major component of plasma proteins responsible for
reversible drug binding ■ Class I drugs: If the dose of drug is less than the binding
■ Widely distributed capacity of albumin, then the dose/capacity ratio is low.
■ Elimination half-life = 17 to 18 days ■ The binding sites are in excess of the available drug, and the
■ Responsible for maintaining osmotic pressure of the blood bound-drug fraction is high.
and for the transport of endogenous and exogenous ■ This is the case for Class I drugs, which include the majority
substances. ■ Class II drugs: These drugs are given in doses that greatly
■ Acidic exceed the number of albumin binding sites.
Aspartic, Glutamic, Tyrosine ■ The dose/capacity ratio is high, and a relatively high
■ Basic proportion of the drug exists in the free state, not bound to
Histidine, Arginine, Lysine albumin
Examples ■ most of the drug is sequestered on albumin and is inert in
 Salicylates, Phenylbutazone Penicillin terms of exerting pharmacologic actions. If a sulfonamide is
administered, it displaces warfarin from albumin, leading to a
rapid increase in the concentration of free warfarin in plasma,
because almost 100 percent is now free, compared with the
initial small percentage
CLINICAL SIGNIFICANCE OF DRUG-PROTEIN BINDING
■ The plasma protein concentration is controlled by a number
of variables including:
1. protein synthesis
2. protein catabolism
3. Distribution of albumin between intravascular and
extravascular space
4. Excessive elimination of plasma protein, particularly albumin
Binding of drug
■ Can be displaced by other drugs
■ Delays urinary excretion of drugs
■ Increases elimination half-life
■ limited
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 Biopharmaceutics and Pharmacokinetics
Topic 3 | Membrane Transport

MECHANISMS OF TRANSPORT ACROSS ION-PAIR TRANSPORT

MEMBRANES

PASSIVE DIFFUSION o hypothetical mechanism to permit

passive transport (diffusion) of highly
ionized molecules through cell
o the major mechanism for the transport membranes
of most (uncharged) molecules across - hypothetical because they were
cell membranes able to diffuse by passive diffusion
o only uncharged (neutral) molecules can into the cell membrane but it has
cross the hydrophobic cell membrane to undergo “pairing”
by passive diffusion o requires pairing of charged molecules
o diffusion requires a concentration (drugs) with “carrier” molecules of
gradient (transfer of molecules from equal but opposite charges to form a
higher concentration to lower neutral complex that can passively
concentration) diffuse through the lipid membrane
o no external energy is expended: no - only two pairings can happen
need carrier in order to get inside the o requires carrier molecules (ion-pairs)
cell o saturable (limited by number of
o drug molecules move forward and carriers)
backward across a membrane o requires concentration gradient
o rate of diffusion is dependent upon - It cannot diffuse inside the cell by
(limited by): passive diffusion all at once. It has
-concentration gradient to follow concentration gradient
-surface area available for transport from higher to lower
concentration.

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 Biopharmaceutics and Pharmacokinetics
Topic 3 | Membrane Transport

BULK FLOW VESICULAR TRANSPORT

o mechanism of movement of all types of o mechanism of transport of highly

molecules between cells. (Unrestricted charged or very large molecules across

by size or charge) cell membranes

- It is a type of movement, into the o it is the only transport mechanism that

cell, inside the cell, in between cell. does not require a drug to be in an

o avoids transport across or through cell aqueous solution to be absorbed

membrane barriers (a movement o transport of molecules across the cell

occurs through intercellular clefts or membrane due to formation of

gaps) : diffusion of the molecules is not membrane vesicles that encapsulate

going to happen on the cell the (charged, large) molecules and

membrane. It is going to happen in move the molecules through the

between gaps from one cell to another membrane

cell. o Does require a carrier in order for the

o very rapid transport drug to get inside but it doesn’t need

o not saturable (not requires carrier) to be in solution.

o requires concentration gradient

▪ PHAGOCYTOSIS
-engulfment of large solutes/fluids
▪ PARACELLULAR ABSORPTION
-cell eating
- diffusion of molecules is going to
▪ PINOCYTOSIS
happen in between gaps of two cells
-engulfment of small particles or
micromolecules
▪ TRANS-CELLULAR ABSORPTION
-cell drinking
- diffusion or absorption of molecules
▪ ENDOCYTOSIS
happen across the cell membrane
-moving macromolecules into the cell
▪ EXOCYTOSIS
-moving macromolecules outside the
cell

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 Biopharmaceutics and Pharmacokinetics
Topic 3 | Membrane Transport

CARRIER MEDIATED TRANSPORT

• FACILITATED TRANSPORT
• ACTIVE TRANSPORT - mechanism to permit transport of
- mechanism to permit transport of charged molecules too large to pass
through protein pores through the
charged molecules too large to pass
cell membrane
through protein pores through the - usual carrier molecule are the water
cell membrane molecules, the globular proteins
- does not require energy (ATP)
- requires a specific carrier molecule does carrier
require energy (ATP) as a carrier - requires concentration gradient
(transport of a drug inside the cell
- Does not require following
requires concentration gradient. It
concentration gradient. has to follow from higher to lower
- Able to transport against a concentration)
- Cannot transport against a
concentration gradient. concentration gradient.
- saturable (limited by number of carrier - saturable
- subject to competitive inhibition
molecules)
- subject to competitive inhibition
(endogenous or exogenous
molecules)

▪ Endogenous molecules
: Substances inherent or
biomolecules inherent to the
body. It’s being produced by the
body.
▪ Exogenous molecules
: Not inherent to the body.
Something that should eat in
order to have that kind of
molecules

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